Computational Study of the Effects of AF-related Genetic Mutations in 3D Human Atrial Model

Abstract

Atrial fibrillation (AF) is the most frequent atrial rhythm disorder with an incidence increasing with age. Genetic mutations impairing the normal functioning of IKr and Ito channels are implicated in AF outbreaks in healthy patients. The higher susceptibility to AF in presence of KCNH2 T436M, KNCH2 T895M and KCNE3-V17M mutations was previously studied by simulating their effects on atrial electrophysiology in single-cell and tissue. This work aims at extending the previous study to a 3D hiatrial model to assess vulnerability to AF initiation and maintenance on a complex geometry. A realistic model of human atria was used to run 3D simulations and study temporal vulnerability. After stabilization, a train of stimuli was applied to the coronary sinus region to simulate an ectopic stimulus and to induce arrhythmia. The results show a higher susceptibility of the mutant atria to develop arrhythmias in a mutation-dependent fashion. The KCNE3-V17M variant was the most proarrhythmogenic with a 24ms-wide vulnerable window(VW) and instable arrhythmic patterns. The KCNH2 T895M and KCNH2 T436M mutations presented a VW of 7ms and 10ms, respectively, with mainly macro re-entries. These findings highlight the different effects of the genetic mutations and the importance of a patient-specific approach.